Bazedoxifene acetate formulations

Abstract

The present invention is directed to solid dispersions of bazedoxifene acetate, compositions containing the same, preparations thereof, and uses thereof.

1 . A solid dispersion comprising bazedoxifene acetate dispersed in a dispersing agent.  
     
     
         2 . The solid dispersion of  claim 1  wherein said bazedoxifene acetate in said solid dispersion is amorphous.  
     
     
         3 . The solid dispersion of  claim 1  wherein said dispersing agent comprises a cellulose, hyaluronate, alginate, polysaccharide, heteropolysaccharide, poloxamers, poloxamines, ethylene vinyl acetate, polyethylene glycol, dextran, polyvinylpyrrolidone, chitosan, polyvinylalcohol, propylene glycol, polyvinylacetate, phosphatidylcholines, miglyol, polylactic acid, polyhydroxybutyric acid, mixtures of two or more thereof or copolymers thereof.  
     
     
         4 . The solid dispersion of  claim 3  wherein said dispersing agent comprises polyvinylpyrrolidone, poloxamer or polyethylene glycol.  
     
     
         5 . The solid dispersion of  claim 4  wherein said dispersing agent comprises polyvinylpyrrolidone.  
     
     
         6 . The solid dispersion of  claim 4  wherein said dispersing agent comprises Poloxamer 188.  
     
     
         7 . The solid dispersion of  claim 4  wherein said dispersing agent comprises PEG 1450.  
     
     
         8 . The solid dispersion of  claim 1  wherein the weight ratio of bazedoxifene acetate to dispersing agent is about 1:99 to about 75:25.  
     
     
         9 . The solid dispersion of  claim 1  wherein the weight ratio of bazedoxifene acetate to dispersing agent is about 1:99 to about 60:40.  
     
     
         10 . The solid dispersion of  claim 1  wherein the weight ratio of bazedoxifene acetate to dispersing agent is about 1:99 to about 10:90.  
     
     
         11 . The solid dispersion of  claim 1  wherein the weight ratio of bazedoxifene acetate to dispersing agent is about 5:95.  
     
     
         12 . The solid dispersion of  claim 1  wherein the weight ratio of bazedoxifene acetate to dispersing agent is about 40:60 to about 60:40.  
     
     
         13 . The solid dispersion of  claim 1  wherein the weight ratio of bazedoxifene acetate to dispersing agent is about 1:1.  
     
     
         14 . The solid dispersion of  claim 1  having an equilibrium solubility in 0.0005 M acetic acid at a temperature of about 20 to about 26° C. of at least about 8 mg/mL.  
     
     
         15 . The solid dispersion of  claim 1  wherein a dosage form comprising about 10 mg total of bazedoxifene acetate in the form of said solid dispersion is characterized by an AUC 0-24  greater than about 140 ng·hr/mL when orally administered to mammal.  
     
     
         16 . The solid dispersion of  claim 1  wherein a dosage form comprising about 10 mg total of bazedoxifene acetate in the form of said solid dispersion is characterized by: 
 a) an AUC 0-24  of about 140 to about 250 ng·hr/mL;    b) a C max  of about 12 to about 30 ng/mL; and    c) a t max  of about 1.0 to about 3.5 hr;    when orally administered to mammal.    
     
     
         17 . A method of preparing the solid dispersion of  claim 1  comprising: 
 a) combining bazedoxifene acetate and said dispersing agent in solution, wherein said solution comprises a solvent; and    b) removing said solvent to yield said solid dispersion.    
     
     
         18 . The method of  claim 17  wherein said solvent is an organic solvent.  
     
     
         19 . The method of  claim 18  wherein said organic solvent comprises an alcohol.  
     
     
         20 . The method of  claim 19  wherein said alcohol comprises ethanol.  
     
     
         21 . A solid dispersion prepared by the method of  claim 17 .  
     
     
         22 . A method of preparing the solid dispersion of  claim 1  comprising: 
 a) combining bazedoxifene acetate with melted dispersing agent to form a liquid mixture; and    b) solidifying said liquid mixture to form said solid dispersion.    
     
     
         23 . The method of  claim 22  wherein said melted dispersing agent is prepared by heating said dispersing agent to a temperature above about 30° C.  
     
     
         24 . The method of  claim 22  wherein said solidifying is carried out by cooling said liquid mixture to a temperature at or below about 25° C.  
     
     
         25 . A solid dispersion prepared by the method of  claim 22 .  
     
     
         26 . A composition comprising the solid dispersion of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         27 . The composition of  claim 26  comprising about 1 to about 99% by weight of said solid dispersion.  
     
     
         28 . The composition of  claim 26  comprising about 1 to about 50% by weight of said solid dispersion.  
     
     
         29 . The composition of  claim 26  comprising about 1 to about 30% by weight of said solid dispersion.  
     
     
         30 . The composition of  claim 26  comprising about 1 to about 20% by weight of said solid dispersion.  
     
     
         31 . The composition of  claim 26  comprising about 1 to about 10% by weight of said solid dispersion.  
     
     
         32 . A dosage form comprising the solid dispersion of  claim 1 .  
     
     
         33 . The dosage form of  claim 32  wherein said dosage form is for oral, transdermal, or implantation administration.  
     
     
         34 . The dosage form of  claim 32  wherein said dosage form is a tablet or capsule.  
     
     
         35 . A method of treating a mammal having a disease or syndrome associated with estrogen deficiency or excess of estrogen comprising administering to said mammal a therapeutically effective amount of the solid dispersion of  claim 1 .  
     
     
         36 . A method of treating a mammal having a disease or disorder associated with proliferation or abnormal development of endometrial tissues comprising administering to said mammal a therapeutically effective amount of the solid dispersion of  claim 1 .  
     
     
         37 . A method of lowering cholesterol in a mammal comprising administering to said mammal a therapeutically effective amount of the solid dispersion of  claim 1 .  
     
     
         38 . A method of inhibiting bone loss in a mammal comprising administering to said mammal a therapeutically effective amount of the solid dispersion of  claim 1 .  
     
     
         39 . A method of treating breast cancer in a mammal comprising administering to said mammal a therapeutically effective amount of the solid dispersion of  claim 1 .  
     
     
         40 . A method of treating postmenopausal woman for one or more vasomotor disturbances comprising administering to said postmenopausal woman a therapeutically effective amount of the solid dispersion of  claim 1 .  
     
     
         41 . The method of  claim 40  wherein said vasomotor disturbance is hot flush.